Kala Azar (Visceral Leishmaniasis

Visceral leishmaniasis (VL),
also known as kala azar, is a
worldwide protozoal vectorborne disease, endemic in
47 countries and putting
approximately 200 million
people at risk of infection. The
annual incidence is estimated
to be 500,000 cases, with
90% occurring in India,
Bangladesh, Nepal, Sudan,
and Brazil, (and 60% in the
Indian subcontinent alone).
The disease often affects the
poorest populations. This is
the second largest cause of
parasitic death, characterized
by fever, weight loss,
hepatosplenomegaly, anemia
and a depression of the
immune system. Without
treatment, nearly all patients
will die. Death can be avoided
by timely treatment, even in
basic field circumstances.

Different species of the
Leishmania parasite causing
the disease are transmitted
by the phlebotomine sandfly.
Both animals and humans
can act as the parasite’s
reservoir. Post kala azar
dermal leishmaniasis
(PKDL) appears as a rash
that occurs after or during
VL infection and treatment.
It can be highly infectious as
parasites may be present in
the raised areas of the skin,
acting as a reservoir for
anthroponotic VL (ie,
transmission by sandfly bite
from PKDL patient to new
patient) between epidemic
cycles.

Epidemics associated with
high mortality are frequent
where conditions such as
complex emergencies, mass
migration, high rates of HIV
and poor nutritional status
accelerate the development
and spread of the disease,
and where many patients do
not have access to treatment.
The recent (end 2009)
outbreak in South Sudan
involved ~1,000 patients, and
is considered the start of a
much larger re-emerging
epidemic in the region.
A major challenge is coinfection of VL and HIV. Both
diseases influence each other
in a vicious spiral: HIV
patients are much more
susceptible to develop kala
azar, and once infected, kala
azar accelerates the onset of
full-blown AIDS.

Initial screening relies on
history of prolonged fever
and clinical splenomegaly.
Clinical suspect patients can
be investigated for VL using
rK39 antigen-based rapid
diagnostic test (RDT). RDTs
only require a drop of the
patient’s blood. In suspect
cases with negative RDT
result, VL can be either ruled
out (in areas where rK39
RDT have proved to be
highly sensitive) or further
searched by another
serological test (e.g. the
DAT) or by microscopic
examination of spleen, bone
marrow or lymph node
aspirates. These techniques
require technical expertise
and laboratories that are
often not available in areas
where most patients are.
ELISA and IFAT tests have
been developed for the
diagnosis of VL, however
their use is limited in the field
as a well-equipped
laboratory and skilled
personnel are required.

TREATMENT
Current treatment options
include pentavalent
antimonials (Pentostam®,
generic SSG, Glucantime®),
amphotericin B deoxycholate,
liposomal amphotericin B
(AmBisome®), paromomycin
and miltefosine. Combination
therapies will be available in
the near future. Although the
list of treatment options seems
extensive, each has significant
limitations.
Pentavalent antimonials, given as
daily intramuscular injection for 30
days, is used as first line therapy in
most countries. It is still effective in
most endemic areas. However,
there is a 60% failure rate to this
medication in Bihar State, India.
It can cause serious toxic side
effects, and is poorly tolerated in
elderly, moribund, pregnant and
HIV co-infected patients, with
mortality being significantly higher
than in non HIV-infected.
Miltefosine is contraindicated
during pregnancy, and should
ideally be taken in combination in
order to avoid the development of
drug resistance. The treatment in
monotherapy is 28 days so
adherence to non-directly
observed treatment is another
barrier and can also contribute to
drug resistance.
Paromomycin is administered
intramuscularly for 21 days, which
may trigger lack of adherence. This
is the cheapest available drug.

While its efficacy is high in India,
it is less in East Africa where
higher dosage or use in
combination will be required.
Amphotericin-B deoxycholate is
a cumbersome treatment that
needs to be given in slow IV
infusions daily or every other
days for 14 doses. Careful
hydration and potassium intake
are needed to avoid renal
toxicity and hypokalemia.
AmBisome is used as secondline therapy for patients in East
Africa, once SSG fails. In India,
given the high levels of
resistance to antimonials, it is
the best first-line therapy option
on a regimen of 20 mg/kg b.w.
divided over 5 infusions with an
excellent tolerability, safety and
efficacy. It can be used in
pregnant women. However, its
current cost remains an
important barrier to treatment.
The treatment landscape is
evolving, and treatment
regimens are being simplified.
Studies showing efficacy and
safety of AmBisome at a
reduced dose (single shot
10 mg/kg. b.w.) in the Indian
subcontinent are promising.
Results of combination
treatment studies are also
anticipated, with the intent to
(1) reduce the risk of the
parasite developing resistance
to the drugs, (2) optimize the
efficacy and safety of treatment,
and (3) reduce costs and
hospitalization time.